Cardiac Isoenzymes Following Heart Transplantation* joseph S. Ladouiski, M.D., F.G.G.R; Margaret Sullivan, R.N.; Michael H. Schatzlein, M.D., F.G.G.R; Alan G. Peterson, M.D., F.G.G.R; David] Underhill, M.D., F.C.C.R, and Ronald H. Scheeringa, M.D. Creatine phosphokinase (CPK) isoenzymes are commonly obtained after heart transplantation (HT) to assess myocardial injury of the donor heart. This investigation retrospectively evaluated the utility of this practice. Fifty-six recipients of orthotopic heart transplants had at least two daily CPK-MB studies following UT. All patients were followed up for at least one year (or until death). Nineteen patients had entirely negative CPK-MB determinations (NEG). Eighteen patients had a single positive CPK-MB determination, and were considered to be equivocal (EQUIV). Nineteen patients had more than one daily positive CPKMB determination (POS). To evaluate the influence of positive CPK-MB determinations on the outcome of HT, we compared the results in the NEG and POS groups. There was no difference in the donor organ ischemic times between the two groups. The duration of follow-up for the two groups was also similar (1,192 days vs 1,020 days). The

of the creatine phosphokinase (CPK)-MB Release isoenzyme has been shown to be a useful indicator of irreversible myocardial injury in experimental'< and clinical" practice. CPK-MB levels are routinely used to detect myocardial injury following myocardial infarction, cardiac surgery, and cardiac trauma. By extrapolation from this experience, CPKMB levels have been used to determine whether myocardial injury occurs during heart transplantation. This study was undertaken to assess whether myocardial injury following heart transplantation, as determined by CPK-MB serum levels, was related to the eventual development of rejection, pacer dependence, coronary artery disease (CAD), or mortality. MATERIALS AND METHODS

lbtients

Fifty-six heart transplant recipients had two daily CPK-MB level determinations, beginning on the first posttransplant day. If an MB level confirmed myocardial injury, subsequent daily levels were obtained until a negative determination was obtained. No patient was receiving lovastatin at the time of transplantation. The patients had their transplants between July 1985 and February 1990. All recipients were followed up for at least one year or until death. Creatine phosphokinase and MB bands were determined photometrically (with the ACA-3 [DuPont] or the Paramax [Baxter] instrument). In the event that the CPK level exceeded 450 IV, an *From the Northern Indiana Heart Institute, Fort Wayne, Ind. Presented at the 57th Annual Scientific Assembly, American College of Chest Physicians, San Francisco, November 4-8, 1991. Manuscript received November 4, 1991; revision accepted March 19. Beprin: requests: Dr. Ladouiski, Indiana/Ohio Heart, 7910 mst Jefferson Blvd, Fort Wayne, Indiana 46804

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NEG and POS groups had no signi6cant difference in: 1 year survival (84 percent vs 74 percent); freedom from treated rejection episodes in 3 months (39 percent vs 42 percent); and freedom from coronary artery disease (CAD) at 3 years (83 percent vs 86 percent). Additionally, the ejection fractions of the donor hearts were similar at 1 year post-transplant for the 2 groups (64 percent vs 59 percent). We conclude that myocardial injury, as reSected by post-transplant CPK-MB levels, does not predict oneyear mortality, predisposition to rejection, predisposition to coronary artery disease, or ultimate graft dysfunction. In an effort to perform HT more economically, we no longer obtain CPK-MB levels (oUawing UT. (Cheat 1992; 102:1520-21)

I

CAD = coronary artery disease; CPK = creatine phosphokinase

I

MB level in excess of 2.2 percent was considered positive. In the event that the CPK level was less than (or equal to) 450 IV, an MB level of greater than 8 IV was considered positive. Statistical analysis was performed by analysis of variance (ANOVA) for numeric variables and by Pearson Xlfor categoric variables. Actuarial analysis was done by log-rank and Wilcoxon analysis of Kaplan-Meier estimations. RESULTS

Nineteen patients had entirely negative CPK-MB determinations (NEG). Nineteen patients had more than one daily positive CPK-MB determination, indicative of significant myocardial injury (POS). A further 18 patients had a single positive daily CPK-MB determination and were thought to constitute an equivocal group. Comparison was therefore made between the unequivocally POS and NEG groups. The two groups (POS vs NEG) did not differ significantly in male:female ratio (10:9 vs 15:4), average age at the time of transplantation (56 years vs 51 years), or average follow-up time (1,020 days vs 1,193 days). For the POS group, 63 percent of the patients' donors had been receiving continuous intravenous inotropic medications prior to heart procurement compared with 84 percent for the NEG group (p = 0.31). The donor hearts in each group were subjected to similar ischemic times (average = 135 min vs 127 min, p = 0.81). During the entire follow-up interval, four of 19 recipients in the POS group required insertion of a permanent pacemaker. One of the 19 recipients in the NEG group required pacer insertion. This difference does not achieve statistical significance (p = 0.15). Cardiac lsoenzymes following HeartTransplantation (Ladowski et 8/)

100

-----II~---___e........

90 80

70 60 ]

50

30

20 10

1 Yr

2 Yr

3 Yr

.. Yr

The one-year survival for the POS group was 74 percent. For the NEG group it was 84 percent, a difference that is not significant. Rejection data are presented in Table 1. When freedom from treated rejection episodes in the first three post-transplant months, average treated rejection episodes during the entire period of follow-up, and death from rejection during entire period offollowup were compared, no significant differences were found between the two groups. Posttransplant CAD was defined as either (1) any luminal irregularities or (2)any new luminal narrowing (or "pruning") when compared with previous angiograms. The results of the annual coronary angiograms are summarized in Figure 1. Log-rank and Wilcoxon analysis of the Kaplan-Meier estimates of freedom from CAD demonstrate no difference between the POS and NEG groups. In addition to the annual coronary angiograms, the average first annual ejection fraction (by ventriculography) was compared for the two groups. There was no significant difference (59 percent POS vs 64 percent NEG, p=O.21). DISCUSSION

Although CPK-MB isoenzyme serum levels are a sensitive indicator of myocardial injury, serum enzyme levels have not been found to be sensitive indicators of incipient cardiac rejection." Only when experimental cardiac rejection is allowed to progress to a terminal stage do CPK levels become markedly elevated." Exclusive of rejection, donor instability and the manTable I-Rejection in the Positive (POS) CPK vs Negative (NEG) CPK Groups

Actuarial freedom from rejection @ 3 mo, % Rejection episodes/patient yr Ultimately fatal rejection, %

POS

NEG

p

42 0.21 16

39 0.22 11

NS NS NS

5 Yr

FIGURE 1. Freedom from coronary artery disease vs time.

datory ischemic time related to procurement and implantation might cause myocyte injury within the donor heart. This study was undertaken to assess whether this injury; as determined by CPK-MB levels, had any prognostic value for outcome after heart transplantation. We therefore studied mortality, oneyear ventricular function, and pacer dependence as potential complications of significant myocardial injury. Additionally, we investigated whether perioperative myocardial injury made a recipient more likely to develop long-term rejection or CAD. CONCLUSION

Myocardial injury at the time of heart transplantation, as indicated by CPK-MB levels, is not related to treatment of the donor with intravenous inotropic agents or to the ischemic time of the donor heart. Peritransplant myocardial injury, as indicated by CPK-MB levels, does not predict ultimate pacer dependence of the recipient, development of rejection, development of CAD , one-year mortality, or oneyear left ventricular dysfunction. In an effort to perform heart transplantation more economically, we no longer obtain routine CPK-MB levels following heart transplantation. REFERENCES

1 Ahmed SA, Williamson JR, Roberts R, Clark RE, Sobel BE. The association of increased plasma MB CPK activity and irreversible ischemic myocardial injury in the dog. Circulation 1976; 54:18793 2 Hearse OS, Humphrey SM. Enzyme release during myocardial anoxia: a study of metabolic protection. J Mol Cell Cardiol 1975; 7:463-82 3 Smith AF, Wilkinson JH. Tissue Isoenzymes. In: Hearse OJ, Deleiris J, eds. Enzymes in cardiology: diagnosis and research. New York: John Wiley, 1979 4 Stinson EB, Doug E, Bieber C~ Schroeder JS, Shumway NE. Cardiac transplantation in man. JAMA 1969; 207:2233-42 5 Semb BKH, Stromme JH. Serum enzyme changes during modified cardiac rejection in dogs. Scand J Thorac Cardiovasc Surg 1972; 6:327-31

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